DESCRIPTION: (Applicant's Description) Approximately 800,000 new skin cancers occur in the U.S. annually that represent a major economic burden to our health care system. Skin cancers have been shown to be related to UV light exposure. Of the key biochemical changes that occur, polyamine biosynthesis is consistently associated with tumor promotion. Interference with polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) enzyme with difluoromethylornithine (DFMO) reduces skin cancer formation. DFMO has been shown to inhibit ODC induced by phorbol esters applied to human skin. The proposal is designed as a phase 3 study of DFMO. The first step will be a 4 week placebo run-in study in 334 subjects to assess compliance and eliminate noncompliers (estimated at 15%). The second step is a placebo-controlled, double-blinded randomized study of DFMO in 284 (est.) subjects with a history of basal or squamous cell skin cancer. Subjects will be randomized to placebo or DFMO for an average of 4 years (range 3-5 years). Over the treatment period, about 40% of subjects will be expected to develop new skin cancers. Inhibition of 50% of all new skin cancers is anticipated. Hearing will be monitored clinically and by audiogram. Skin polyamine levels and ODC induction by TPA will be measured at start of study in all randomized subjects, in random samples of 60 subjects on each arm at 2, 3 and 4 years, and in normal skin of subjects who develop skin cancers. This study will be a pivotal trial of the efficacy of DFMO and the associated intermediary biologic markers, ODC and polyamine levels,